Environmental, metabolic and teratogenic factors have been suggested as possible etiological factors in congenital skeletal defects of the lower limb: caudal regression syndrome or sacral agenesis. However, very little is known about the genetic factors important in predisposing infants to defective embryogenesis in disorders with multifactor etiologies. Initial studies of children with sacral agenesis demonstrated that 5/9 patients responded poorly in mixed lymphocyte culture (MLC) to one patient, KL, despite differences at the HLA-D locus. These studies suggest the existence of a disease-associated lymphocyte activating determinant detectable by MLC testing. It is proposed that this determinant may be the analog of T/t locus in the mouse which controls cell-cell interactions and cellular differentiation during embryogenesis. Studies are planned to examine the association of this disease-associated lymphocyte activating determinant with genes of the HLA system (HLA-D and HLA-DR) and other sixth chromosomal genes (Factor B, PGM3 and GLO) to more precisely define its chromosomal relationships with the histocompatibility system. The occurrence of this disease-associated lymphocyte activating determinant will be examined in family members of sacral agenesis patients and the normal population using KL's lymphocytes as testing cells. These test cells will be used to explore the presence of this determinant in patients with birth defects of the neural tube, spina bifida, which would support the hypothesis that this determinant may be a gene product(s) of the proposed T/t analog complex.